Kucaba, Tamara A.

Abstract Description Sepsis, the life-threatening organ dysfunction stemming from the severe inflammatory response to systemic microbial infection, can affect humans of any age. One consequence of sepsis is the development of prolonged immunoparalysis that contributes to increased susceptibility to infection. With vaccination being an important means for protecting humans from infection throughout their lifetime, it is surprising that there has been no study performed to date assessing vaccine efficacy in sepsis survivors. We found neonatal and adult mice given an intramuscularly delivered inactivated multivalent influenza vaccine 30 days after sepsis induction had reduced total and class switched Ab titers, compared to non-septic controls. The reduced humoral response was due, in part, to impaired CD4 T cell and B cell responses to the vaccine. Reduced Ab titers were similarly seen in post-septic mice given an intranasal live-attenuated influenza vaccine. ELISpot data demonstrating reduced numbers of antibody secreting cells in the spleens of vaccinated septic mice further support the ELISA results. Moreover, mice vaccinated prior to sepsis induction also showed reduced antibody titers. Importantly, vaccinated septic mice had reduced protection to a lethal influenza challenge, demonstrated by increased mortality and viral burden in the lungs. These data collectively show how sepsis can lead to increased susceptibility to pathogens normally neutralized by vaccine-induced immunity. Funding Sources Supported by NIH/NIAID R35 GM140881; 5R01 GM139046; 1T32TR004385 Topic Categories Translational and Interventional Immunology (TI)

Abstract The impact of microbes on restraining the immune response to allergens has been extensively studied and is a key element of the hygiene hypothesis. Lung type 2 innate lymphoid cell responses to airway allergens can be inhibited by administration of a number of microbial products; however, it is unclear whether such an effect would be observed with natural infections and how sustained any observed inhibitory effects would be. To answer these questions, we used a murine model of physiological microbial exposures through cohousing SPF laboratory mice with pet store mice and examined the acute type 2 response to intranasally delivered fungal allergen extract Alternaria alternata. We found laboratory mice cohoused with pet store mice for two weeks display a suppressed ILC2 response to A. alternata which resulted in reduced eosinophilia. By comparison, mice cohoused for at least two months had ILC2 and eosinophil responses similar to SPF mice despite dramatic changes to the composition of the immune cell populations in the lungs. Lung ILC2 in two-month cohoused mice were still sensitive to subsequent inflammatory cues, as administration of poly(I:C) was able to suppress ILC2 activation and eosinophilia equally well in SPF and two-month cohoused animals. These findings suggest ILC2 dynamically respond to their environment and are not easily desensitized long-term.